In 1998, Glinka A. et. al. published a research article in Nature (Nature, 1998; 391(6665):357-362), which claims that they have found a new secretory protein in the research work of the embryo development of Xenopus laevis, which is called dickkopf-1 (dkk-1). Their research confirms that dkk-1 is the inhibitory factor of Wnt signaling pathway and is “inducer” formed in the “head induction” during the embryonic development of Xenopus laevis. Later, in 1999, Fedi P., et. al. (J Biol Chem, 1999; 274(27):19465-72) isolated human homologous gene of dkk-1 from human leiomyosarcoma cell SK-LMS-1 and the corresponding cDNA library by conditioned chromatogram and PCR. The mRNA transcript is about 2 kb, encoding 266 amino acids. Since then, the scientists for the first time reveal the molecular mechanism of DKK-1 as Wnt signaling pathway inhibitor through near 5 years of research work.
During the research work of the function and action mechanism of DKK-1, the scientists also notice that DKK-1 is relevant to certain human diseases, such as osteoporosis (Biochem Biophys Res Commun, 2004; 318(1):259-264. N Engl J Med, 2002; 346(20):1513-1521), bone damage caused by multiple myeloma (N Engl J Med, 2003; 349(26):2483-2494) and other human malignancy. For example, Mikheev A M et. al. (Carcinogenesis, 2004; 25(1):47-59) established 2 non-tumorigenic revertant cell lines with human cervical cancer Hela cell line, and found by cDNA chip that DKK-1 is highly expressed in the above 2 non-tumorigenic revertant cell lines and that lack of DKK-1 expression is necessary for Hela tumogenicity. Therefore, DKK-1 is deemed as a candidate cancer inhibitory gene. Furthermore, Wirths O et. al. (Lab Invest, 2003; 83(3):429-434) use “suppression subtractive hybridization approach” to find that DKK-1 is highly expressed in children hepatoblastoma and Wilms' tumor. The result shows that 26 out of 32 children hepatoblastomas highly express DKK-1 ( 26/32, 81%), 5 out of 6 Wilms' tumors highly express DKK-1 (⅚, 83%). However, only 2 out of 20 liver cancer patients highly express DKK-1 ( 2/20, 10%), and 1 out of 5 medulloblastoma cell lines highly express DKK-1 (⅕, 20%). There is no DKK-1 expression in malignant gliomas and breast cancers.
Therefore, there is urgent need for the precise and specific diagnosis of particular cancers.